Renal control of sodium excretion is a critical factor in determining long-term regulation of blood pressure. The Dahl salt sensitive (DS) rat is a well-established animal model of salt-sensitivity that has many of the characteristics of human hypertension that is common in African Americans. We have observed that DS rats have an exaggerated blood pressure response to an acute stress and this is exacerbated by a high fat diet. Studies from Project 1 investigators have shown that African Americans have a shift in the relationship between arterial pressure and natriuresis during an acute stress protocol such that blood pressure is inappropriately high relative to the sodium excretion. When given a high salt diet, the DS rat develops hypertension due to its inability to appropriately excrete a salt load. In recent years, our laboratory has generated considerable evidence that the renal endothelin B (ETB) receptor plays a critical role in promoting the excretion of an acute and chronic salt load by activation of nitric oxide synthase 1 (NOS1). Lack of ETB receptor function leads to endothelial dysfunction and salt sensitive hypertension in various animal models. To the contrary, treatment with an ETA receptor antagonist will lower blood pressure in salt-dependent models of hypertension such as the DS rat. We have hypothesized that an imbalance between ETA and ETB mediated actions contributes to salt-dependent hypertension and associated changes in renal and vascular function. We further hypothesize that the endothelin and renin-angiotensin-aldosterone systems play a role in modulating renal excretory function following stress-induced changes in blood pressure. Surprisingly little is known about the influence of obesity on the ability of the kidney to excrete salt especially in the context of environmental stress. The overall hypothesis of the current proposal is that an imbalance of ETA/ETB receptor function and over activity of the renin-angiotensin-aldosterone system contributes to a reduced ability to excrete salt in the Dahl salt-sensitive rat and that moderate obesity exacerbates this effect. The following aims will address more specific hypotheses. Specific Aim 1: To test the hypothesis that stressinduced pressure natriuresis is facilitated by activation of the ETB/NOS1 pathway and that the ETA and renin-angiotensin-aldosterone pathways attenuate the response in genetically salt-sensitive rats; Specific Aim 2: To test the hypothesis moderate obesity attenuates stress-induced pressure natriuresis in genetically salt-sensitive rats; Specific Aim 3: To test the hypothesis that moderate obesity interferes with the ability of the ETB/NOS1 pathway to promote sodium excretion by increasing oxidative stress. Relevance: A shift in the relationship between arterial pressure and sodium excretion is a well-established hallmark of every form of hypertension. Understanding the mechanisms responsible for pressure-natriuresis in the setting of major risk factors, such as environmental stress and obesity, will be critically important for developing new approaches towards the prevention and treatment of hypertension and related disorders.